Glioblastoma (GBM) is a highly aggressive hypervascularized brain tumor characterized by high recurrence rates and poor prognosis despite advanced treatment. The vasculature of GBM is fundamentally different from that of normal vasculature and offers a unique target for anti-cancer therapy. Therefore, direct targeting of tumor vasculature with vascular disrupting agents (VDAs) is distinctly different from anti-angiogenic strategies, and offers a complementary approach to standard therapies. Combretastatin A4 (CA4) is a potent vascular disrupting drug. CA4 induces rapid shutdown of tumor blood supply, typically promoting a necrosis at the core of the tumor, but leaves a rim of viable tumor cells at the periphery which can then rapidly re-grow. However, CA4 is not effective in inducing necrosis at the core of GBM tumor. The ineffectiveness of small molecule chemotherapy drugs in treating malignant brain tumors has been attributed to the blood-brain barrier (BBB) being a significant impediment to the transvascular extravasation of drug fraction across the barrier into the extravascular compartment of tumor tissue and the high tumor interstitial fluid pressure also presents an additional delivery barrier. Nanotechnology is already benefiting to deliver drugs across the BBB and into brain tumors. We have engineered a nano-sized polymeric CA4 conjugate which demonstrates high water solubility. Preliminary intravenous (i.v.) delivery of G3-CA4 in an orthotopic glioma model demonstrated necrosis at the core of the tumor leaving a rim of viable tissue. By applying the designed nanoprodrug strategy and tumor- specific prodrug activation mechanism, we observed the true success of inducing necrosis at the core of the tumor in an orthotopic U-251 glioma animal model first time. Tumor-VDAs have significant potential when combined with cytotoxic chemotherapy and radiotherapy in treating other tumor models. Combined treatment with radiation is attractive, as radiation therapy (RT) represents a standard of care and RT should effectively kill the well-oxygenated cancer cells in the well-perfused tumor rim. We have shown that GBM cancer stem cells are sensitive to radiation exposure in culture and a single dose of 50Gy irradiation yielded necrosis in primary GBM rat model. Therefore, this study is extended to include SRS and standard cytotoxic temozolomide (TMZ) therapies with G3-CA4. We hypothesize that the combination of G3-CA4 with SRS and TMZ will show synergistic cytotoxic effect in clinical relevant primary GBM model. Our objectives of the proposed research are A) To incorporate CA4 molecules with dendrimer-based nanoparticles (G3-CA4) that demonstrates full solubility in aqueous media, B) To determine the efficacy and safety of small molecule CA4, CA4-P and G3-CA4 nanoprodrug in U251 glioma tumor model, C) To determine the efficacy and safety of G3- CA4 alone or in combination with SRS in primary GBM, D) To determine the efficacy and safety of a combined G3-CA4 and standard TMZ therapy in primary GBM model. The overall therapeutic effect from G3-CA4 alone or in combination with SRS/TMZ will be evaluated by image-guided MRI monitoring of long-term survival rats.